HIV vaccine development

An HIV vaccine is a hypothetical vaccine against HIV, the etiological agent of AIDS. As there is no known cure for AIDS, the search for a vaccine has become part of the struggle against the disease.

The urgency of the search for a vaccine against HIV stems from the AIDS-related death toll of over 25 million people since 1981. Indeed, in 2002, AIDS became the primary cause of mortality due to an infectious agent in Africa.

Alternative medical treatments to a vaccine do exist. Highly active antiretroviral therapy (HAART) has been highly beneficial to many HIV-infected individuals since its introduction in 1996 when the protease inhibitor-based HAART initially became available. HAART allows the stabilization of the patient’s symptoms and viremia, but they do not cure the patient of HIV, nor of the symptoms of AIDS. And, importantly, HAART does nothing to prevent the spread of HIV through people with undiagnosed HIV infections. Safer sex measures have also proven insufficient to halt the spread of AIDS in the worst affected countries, despite some success in reducing infection rates.

Therefore, an HIV vaccine is generally considered as the most likely, and perhaps the only way by which the AIDS pandemic can be halted. However, after over 20 years of research, HIV-1 remains a difficult target for a vaccine.

The human body can defend itself against HIV, as work with monoclonal antibodies (MAb) has proven. That certain individuals can be asymptomatic for decades after infection is encouraging.

Difficulties in developing an HIV vaccine

In 1984, after the confirmation of the etiological agent of AIDS by scientists at the U.S. National Institutes of Health and the Pasteur Institute, the United States Health and Human Services Secretary Margaret Heckler declared that a vaccine would be available within two years.

However, the classical vaccination approaches that have been successful in the control of various viral diseases by priming the adaptive immunity to recognize the viral envelope proteins have failed in the case of HIV-1. Some have stated that a HIV vaccine may not be possible without significant theoretical advances.

HIV structure

The epitopes of the viral envelope are more variable than those of many other viruses. Furthermore, the functionally important epitopes of the gp120 protein are masked by glycosylation, trimerisation and receptor-induced conformational changes making it difficult to block with neutralising antibodies.

The ineffectiveness of previously developed vaccines primarily stems from two related factors.

• First, HIV is highly mutable. Because of the virus' ability to rapidly respond to selective pressures imposed by the immune system, the population of virus in an infected individual typically evolves so that it can evade the two major arms of the adaptive immune system; humoral (antibody-mediated) and cellular (mediated by T cells) immunity.
• Second, HIV isolates are themselves highly variable. HIV can be categorized into multiple clades and subtypes with a high degree of genetic divergence. Therefore, the immune responses raised by any vaccine need to be broad enough to account for this variability. Any vaccine that lacks this breadth is unlikely to be effective.

The difficulties in stimulating a reliable antibody response has led to the attempts to develop a vaccine that stimulates a response by cytotoxic T-lymphocytes.

Another response to the challenge has been to create a single peptide that contains the least variable components of all the known HIV strains.

Animal model

The typical animal model for vaccine research is the monkey, often the macaque. The monkeys can be infected with SIV or the chimeric SHIV for research purposes. However, the well-proven route of trying to induce neutralizing antibodies by vaccination has stalled because of the great difficulty in stimulating antibodies that neutralise heterologous primary HIV isolates. Some vaccines based on the virus envelope have protected chimpanzees or macaques from homologous virus challenge, but in clinical trials, individuals who were immunised with similar constructs became infected after later exposure to HIV-1.

There are some differences between SIV and HIV that may introduce challenges in the use of an animal model.

Clinical trials to date

Several vaccine candidates are in varying phases of clinical trials.

Phase I

Most initial approaches have focused on the HIV envelope protein. At least thirteen different gp120 and gp160 envelope candidates have been evaluated, in the US predominantly through the AIDS Vaccine Evaluation Group. Most research focused on gp120 rather than gp41/gp160, as the latter are generally more difficult to produce and did not initially offer any clear advantage over gp120 forms. Overall, they have been safe and immunogenic in diverse populations, have induced neutralizing antibody in nearly 100% recipients, but rarely induced CD8+ cytotoxic T lymphocytes (CTL). Mammalian derived envelope preparations have been better inducers of neutralizing antibody than candidates produced in yeast and bacteria. Although the vaccination process involved many repeated "booster" injections, it was very difficult to induce and maintain the high anti-gp120 antibody titers necessary to have any hope of neutralizing an HIV exposure.

The availability of several recombinant canarypox vectors has provided interesting results that may prove to be generalizable to other viral vectors. Increasing the complexity of the canarypox vectors by inclusion of more genes/epitopes has increased the percent of volunteers that have detectable CTL to a greater extent than did increasing the dose of the viral vector. Importantly, CTLs from volunteers were able to kill peripheral blood mononuclear cells infected with primary isolates of HIV, suggesting that induced CTLs could have biological significance. In addition, cells from at least some volunteers were able to kill cells infected with HIV from other clades, though the pattern of recognition was not uniform among volunteers. Canarypox is the first candidate HIV vaccine that has induced cross-clade functional CTL responses. The first phase I trial of the candidate vaccine in Africa was launched early in 1999 with Ugandan volunteers. The study determined the extent to which Ugandan volunteers have CTL that are active against the subtypes of HIV prevalent in Uganda, A and D.

Other strategies that have progressed to phase I trials in uninfected persons include peptides, lipopeptides, DNA, an attenuated Salmonella vector, lipopeptides, p24, etc. Specifically, candidate vaccines that induce one or more of the following are being sought:

• broadly neutralizing antibody against HIV primary isolates;
• cytotoxic T cell responses in a vast majority of recipients;
• strong mucosal immune responses.

Phase II

On December 13 2004, the HIV Vaccine Trials Network (HVTN) began recruiting for the STEP study, a 3,000-participant phase II clinical trial of a novel HIV vaccine, at sites in North America, South America, the Caribbean and Australia. The trial was co-funded by the National Institute of Allergy and Infectious Diseases (NIAID), which is a division of the National Institutes of Health (NIH), and the pharmaceutical company Merck & Co. Merck developed the experimental vaccine called V520 to stimulate HIV-specific cellular immunity, which prompts the body to produce T cells that kill HIV-infected cells. In previous smaller trials, this vaccine was found to be safe, because of the lack of adverse effects on the patients. The vaccine showed induced cellular immune responses against HIV in more than half of volunteers.

V520 contains a weakened adenovirus that serves as a carrier for three subtype B HIV genes. Subtype B is the most prevalent HIV subtype in the regions of the study sites. Adenoviruses are among the main causes of upper respiratory tract ailments such as the common cold. Because the vaccine contains only three HIV genes housed in a weakened adenovirus, study participants cannot become infected with HIV or get a respiratory infection from the vaccine. It was announced in September 2007 that the trial for V520 would be discontinued after it determined that the vaccination was ineffective. Additionally, it appears that V520 may have made recipients more receptive to infection by HIV-1.

The HVTN expected to finish the study in 2009, but ceased further treatment administration and declared the vaccine ineffective at preventing HIV-infection in September 2007.

The results of the trial have caused some to call for a rexamination of vaccine development strategies.

Phase III

In February 2003, Vaxgen announced that their AIDSVAX vaccine was a failure in North America as there was not a statistically significant reduction of HIV infection within the study population. In November 2003, it also failed clinical trials in Thailand for the same reason. These vaccines both targeted gp120 and were specific for the geographical regions.

There is only HIV vaccine currently in phase III (the NIH/Department of Defense’s ALVAC vCP 1521 canary pox vector/AIDSVAX prime-boost vaccine trial now under way in Thailand).

Planned clinical trials

Novel approaches, including modified vaccinia Ankara (MVA), adeno-associated virus, Venezuelan equine encephalitis (VEE) replicons, and codon-optimized DNA have proven to be strong inducers of CTL in macaque models, and have provided at least partial protection in some models. Most of these approaches are in, or will soon enter, clinical studies.

Economics of vaccine development

A June 2005 study estimates that $682 million is spent on AIDS vaccine research annually.

Economic issues with developing an AIDS vaccine include the need for advance purchase commitment (or advance market commitments) because after an AIDS vaccine has been developed, governments and NGOs may be able to bid the price down to marginal cost.

Future Work

According to Gary J. Nabel of the Vaccine Research Center in Bethesda, Maryland, several hurdles must be overcome before scientific research will culminate in a definitive AIDS vaccine. First, greater translation between animal models and human trials must be established. Second, new, more effective, and more easily produced vectors must be identified. Finally, and most importantly, there must arise a robust understanding of the immune response to potential vaccine candidates. Emerging technologies that enable the identification of T-cell-receptor specificities and cytokine profiles will prove invaluable in hastening this process.

Controversy

Some conservatives, such as Reginald Finger, a member of the Advisory Committee on Immunization Practices (ACIP) in the U.S., have stated that the Committee would have to carefully consider an HIV vaccine's effects on sexual activity. ACIP is a government committee linked to the Centers for Disease Control. ACIP is charged with advising the President on prevention of vaccine-related diseases. Dr. Finger's term expired in June, 2006.

See also

• HIV Vaccine Trials Network
• Subunit HIV vaccine

External links

• Vaccine Research Center (VRC)- Information concerning Preventive HIV vaccine research studies
• NIAID HIV vaccine site (DAIDS)
• Global Alliance for Vaccines and Immunization (GAVI)
• International AIDS Vaccine Initiative (IAVI)
• AIDS Vaccine Advocacy Coalition (AVAC)
• The Pipeline Project - Vaccines in Development (Center for HIV Information at the University of California San Francisco and the HIV Vaccine Trials Network)
• Capital Area Vaccine Effort (CAVE
• Investigation of first candidate vaccine
• Virus Used In HIV Vaccines Weakens Immune System
• Vaccines for Development
• Be the Generation - Information on HIV Vaccine Clinical Research in 20 American Cities
• Australian recruiter for HIV treatment studies
• Aids Vaccine Integrated Project (European Union research programme)
• AIDS.gov - The U.S. Federal Domestic HIV/AIDS Resource
• HIVtest.org - Find an HIV testing site near you
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